Telomere attrition in primary human fibroblasts induces replicative senescence accompanied by activation of the p53 and p16^INK4a/RB tumor suppressor pathways. Although the contribution of p53 and its target, p21, to telomere-driven senescence have been well established, the role of p16^INK4a is controversial. Attempts to dissect the significance of p16^INK4a in response to telomere shortening have been hampered by the concomitant induction of p16^INK4a by cell culture conditions. To circumvent this problem, we studied the role of p16^INK4a in the cellular response to acute telomere damage induced by a dominant negative allele of TRF2, TRF2^ΔBΔM. This approach avoids the confounding aspects of culture stress because parallel cultures with and without telomere damage can be compared. Telomere damage generated with TRF2^ΔBΔM resulted in induction of p16^INK4a in the majority of cells as detected by immunohistochemistry. Inhibition of p16^INK4a with shRNA or overexpression of BMI1 had a significant effect on the telomere damage response in p53-deficient cells. While p53 deficiency alone only partially abrogated the telomere damage-induced cell cycle arrest, combined inhibition of p16^INK4a and p53 led to nearly complete bypass of telomere-directed senescence. We conclude that p16^INK4a contributes to the p53-independent response to telomere damage.